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Opioid Receptor Agonist with Reduced Constipation in Mice

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Opioid Receptor Agonist with Reduced Constipation in Mice fphar-09-01002 August 30, 2018 Time: 10:38 # 1 ORIGINAL RESEARCH published: 31 August 2018 doi: 10.3389/fphar.2018.01002 In vitro and in vivo Pharmacological Activities of 14-O-Phenylpropyloxymorphone, a Potent Mixed Mu/Delta/Kappa- Opioid Receptor Agonist With Reduced Constipation in Mice Roberta Lattanzi1, Silvia Rief2, Helmut Schmidhammer2, Lucia Negri1* and Mariana Spetea2* Edited by: 1 Department of Physiology and Pharmacology “Vittorio Erspamer,” Sapienza University of Rome, Rome, Italy, 2 Department Dominique Massotte, of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck, University of Innsbruck, UPR3212 Institut des Neurosciences Innsbruck, Austria Cellulaires et Intégratives (INCI), France Reviewed by: Pain, particularly chronic pain, is still an unsolved medical condition. Central goals in Stephen Husbands, pain control are to provide analgesia of adequate efficacy and to reduce complications University of Bath, United Kingdom Meritxell Canals, associated with the currently available drugs. Opioids are the mainstay for the treatment Monash University, Australia of moderate to severe pain. However, opioid pain medications also cause detrimental *Correspondence: side effects, thus highlighting the need of innovative and safer analgesics. Opioids Lucia Negri mediate their actions via the activation of opioid receptors, with the mu-opioid receptor [email protected] Mariana Spetea as the primary target for analgesia, but also for side effects. One long-standing focus [email protected] of drug discovery is the pursuit for new opioids exhibiting a favorable dissociation Specialty section: between analgesia and adverse effects. In this study, we describe the in vitro and in vivo This article was submitted to pharmacological profiles of the 14-O-phenylpropyl substituted analog of the mu-opioid Neuropharmacology, agonist 14-O-methyloxymorphone (14-OMO). The consequence of the substitution of a section of the journal Frontiers in Pharmacology the 14-O-methyl in 14-OMO with a 14-O-phenylpropyl group on in vitro binding and Received: 15 June 2018 functional activity, and in vivo behavioral properties (nociception and gastrointestinal Accepted: 14 August 2018 motility) was investigated. In binding studies, 14-O-phenylpropyloxymorphone (POMO) Published: 31 August 2018 displayed very high affinity at mu-, delta-, and kappa-opioid receptors (Ki values in Citation: Lattanzi R, Rief S, Schmidhammer H, nM, mu:delta:kappa = 0.073:0.13:0.30) in rodent brain membranes, with complete Negri L and Spetea M (2018) In vitro loss of mu-receptor selectivity compared to 14-OMO. In guinea-pig ileum and mouse and in vivo Pharmacological Activities vas deferens bioassays, POMO was a highly efficacious and full agonist, being more of 14-O-Phenylpropyloxymorphone, 35 a Potent Mixed Mu/Delta/Kappa- potent than 14-OMO. In the [ S]GTPgS binding assays with membranes from CHO Opioid Receptor Agonist With cells expressing human opioid receptors, POMO was a potent mu/delta-receptor full Reduced Constipation in Mice. Front. Pharmacol. 9:1002. agonist and a kappa-receptor partial agonist. In vivo, POMO was highly effective doi: 10.3389/fphar.2018.01002 in acute thermal nociception (hot-plate test, AD50 = 0.7 nmol/kg) in mice after Frontiers in Pharmacology| www.frontiersin.org 1 August 2018| Volume 9| Article 1002 fphar-09-01002 August 30, 2018 Time: 10:38 # 2 Lattanzi et al. 14-O-Phenylpropyloxymorphone, a Mixed Opioid Agonist subcutaneous administration, with over 70- and 9000-fold increased potency than 14- OMO and morphine, respectively. POMO-induced antinociception is mediated through the activation of the mu-opioid receptor, and it does not involve delta- and kappa- opioid receptors. In the charcoal test, POMO produced fourfold less inhibition of the gastrointestinal transit than 14-OMO and morphine. In summary, POMO emerges as a new potent mixed mu/delta/kappa-opioid receptor agonist with reduced liability to cause constipation at antinociceptive doses. Keywords: pain, analgesia, constipation, opioid agonist, opioid receptor, morphinans, binding affinity INTRODUCTION (Fürst and Hosztafi, 2008; Spetea et al., 2013). Modifications at position 14 of the morphinan skeleton were targeted by Pain, particularly chronic pain, remains an ongoing global health us and others with the prospect of designing novel MOR and socioeconomical problem (Severino et al., 2018), affecting analgesics, which retain their opioid analgesic properties, but more people than cancer, heart disease, and diabetes combined with fewer or no adverse effects (Fürst and Hosztafi, 2008; (Skolnick and Volkow, 2016). Furthermore, comorbidity of Lewis and Husbands, 2011; Spetea and Schmidhammer, 2012; chronic pain with mood disorders (e.g., depression, anxiety) Spetea et al., 2013). We have reported that the introduction in pain patients is well-recognized (Nicholson and Verma, of a 14-methoxy group in oxymorphone leading to 14-O- 2004; Tsang et al., 2008; Miller and Cano, 2009). Opioids methyloxymorphone (14-OMO, Figure 1)(Schmidhammer are the most effective drugs for the treatment of moderate et al., 1984) not only increased binding affinity and agonist to severe pain (Pasternak, 2014; Stein, 2016). However, their potency at the MOR, but also resulted in a significant increase wide use is hampered by unwanted side effects, including in antinociceptive potency in various pain models in rodents constipation, apnea, sedation, nausea, tolerance, and dependence (Schmidhammer et al., 1984; Lattanzi et al., 2005; Spetea (Benyamin et al., 2008; Imam et al., 2018). A huge increase et al., 2010; Dumitrascuta et al., 2017). However, 14-OMO in medical use and abuse of prescription opioids with raised induces the typical opioid-like side effects (Schmidhammer opioid-related morbidity and mortality has been reported et al., 1984; Lattanzi et al., 2005). In this study, we describe in the past years (Skolnick and Volkow, 2016; Severino the in vitro and in vivo pharmacological profiles of the 14- et al., 2018). Ongoing monitoring of pain patients receiving O-phenylpropyl substituted analog of 14-OMO, namely 14-O- opioids to ensure appropriate use and effectiveness is of phenylpropyloxymorphone (POMO, Figure 1), which emerges major importance. The central goal is to balance the patient’s as a new potent mixed mu/delta/kappa-opioid receptor agonist pain relief, potential harmful consequences of opioids, and with reduced propensity to cause constipation at antinociceptive quality of life. Opioids induce their actions via the activation doses. of opioid receptors, that is, mu (MOR), delta (DOR), and kappa (KOR), as members of the large family of G protein- coupled receptors (GPCRs) with seven transmembrane domains MATERIALS AND METHODS (Kieffer and Evans, 2009; Shang and Filizola, 2015). Opioid receptors modulate neurotransmission in neuronal circuits Drugs and Chemicals that subserve pain both at central and peripheral sites (Stein Cell culture media and supplements were obtained from and Machelska, 2011). One long-standing focus of opioid Sigma-Aldrich Chemicals (St. Louis, MO, United States) or drug discovery is the pursuit for safe and effective analgesics Life Technologies (Carlsbad, CA, United States). Radioligands, with more favorable pharmacological features. Different [3H][D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin ([3H]DAMGO), approaches are therefore being evaluated to mitigate the [3H]5a,7a,8b-(-)N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro(4,5) deleterious effects of opioid analgesics, with extended reports dec-8-yl]benzeneacetamide ([3H]U69,593), and guanosine 50-O- into the field over the past years (Stein and Machelska, (3-[35S]thio)-triphosphate ([35S]GTPgS), were purchased from 2011; Aldrich and McLaughlin, 2012; Albert-Vartanian PerkinElmer (Boston, MA, United States). [3H][Ile5;6]deltorphin et al., 2016; Del Vecchio et al., 2017; Günther et al., 2017; II was obtained from the Institute of Isotopes Co. Ltd. (Budapest, Madariaga-Mazón et al., 2017; Schmid et al., 2017; Yekkirala Hungary). Guanosine diphosphate (GPD), GTPgS and opioid et al., 2017; Livingston and Traynor, 2018; Pergolizzi et al., ligands, naloxone, DAMGO, [D-Pen2,D-Pen5]enkephalin 2018). (DPDPE), U69,593 and naltrindole, were obtained from The MOR is the primary target for analgesia, but also Sigma-Aldrich Chemicals (St. Louis, MO, United States). for side effects of opioid analgesics (Pasternak and Pan, Nor-binaltorphimine (nor-BNI) was purchased from Tocris 2013). The present understanding of the MOR function is (Abingdon, United Kingdom). Morphine hydrocloride was persistently increasing with the crystal (active and inactive) obtained from S.A.L.A.R.S. (Como, Italy). Dermorphin and structures of the MOR available (Filizola, 2018). Among clinically deltorphin I were synthesized as previously described (Erspamer used opioids, morphinans including morphine, oxycodone, and et al., 1989; Negri et al., 1992). 14-OMO and POMO were oxymorphone, are of key importance as potent MOR agonists prepared as described earlier (Schmidhammer et al., 1984; Spetea Frontiers in Pharmacology| www.frontiersin.org 2 August 2018| Volume 9| Article 1002 fphar-09-01002 August 30, 2018 Time: 10:38 # 3 Lattanzi et al. 14-O-Phenylpropyloxymorphone, a Mixed Opioid Agonist by liquid scintillation counting using a Beckman Coulter LS6500 (Beckman Coulter Inc., Fullerton, CA, United States). All experiments were performed in duplicate and repeated at least three times. [35S]GTPgS Binding Assays Chinese hamster ovary (CHO) cells
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